The invention relates in general to treatment of atopic, stress related skin disease. In particular, the invention relates to effects of Corticotropin-Releasing Hormone ("CRH") on skin mast cells that result in various skin disorders, and the use of inhibitors and antagonists of CRH to treat such conditions.
CRH is a major regulator of the hypothalamic-pituitary-adrenal axis and principal coordinator of the stress response. While the neuroendocrine release of CRH results in anti-inflammatory effects through activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, recent evidence suggests that CRH is also secreted peripherally and may have pro-inflammatory actions. Immunoreactive CRH (iCRH) has been localized to immune accessory cells in induced aseptic joint inflammation, in streptococcal arthritis, as well as expermental uveitis. CRH can be synthesized locally at inflammatory sites as evidenced by the presence of CRH mRNA in chronically inflamed synovia in rats or released by post-ganglionic sympathetic neurons and sensory afferent fibers. Immunocytochemistry has also verified the presence of iCRH in human tissues undergoing inflammatory processes.
Both iCRH and CRH mRNA have been demonstrated in rat and mouse spleen and thymus, as well as in human peripheral blood leukocytes, while mitogenic stimulation of human T lymphocytes results in synthesis of CRH. However, there is a discrepancy between the abundance of iCRH and the paucity of its mRNA at inflammatory sites in the early, acute phase of inflammation. The demonstration of CRH-like immunoreactivity in the dorsal horn of the spinal cord and dorsal root ganglia, as well as in sympathetic nerve cell bodies and sympathetic ganglia, support the hypothesis that the majority of iCRH in early inflammation is of nerve cell rather than immune cell origin. For purposes of the present invention, it is important that CRH and CRH-receptor mRNA have been identified in human skin (Slominski et al., FEBS Letts., 374:113 (1995)).
CRH administration to humans or animals causes significant peripheral vasodilation manifested as increased blood flow and flushing. Immune CRH also appears to have pro-inflammatory actions as systemic administration of rabbit anti-CRH serum suppressed both the amount of exudate and inflammatory cell accumulation in induced inflammation (Karalis et al., Science, 254: 421(1991)), as well as the severity of experimentally-induced uveitis. Moreover, when this antiserum was administered prior to acute psychological stress, it blocked the resultant activation of dura mast cells (Theoharides et al., Endocrinol. 136:5745 (1995). Analogous to the marked appearance of iCRH, there is activation and proliferation of mast cells at inflammatory sites.
Mast cells are located in the perivascular area close to peripheral nerves and, when activated by nerve stimulation or sensory neuropeptides, they secrete potent vasoactive and proinflammatory mediators including histamine, cytokines, prostanoids and proteases. In fact, tumor necrosis factor (TNF) released from skin mast cells induces both vasodilation and expression of endothelial adhesion molecule-1, while skin mast cell activation by substance P (SP) leads to granulocyte infiltration.
In the light of this background, it is an object of this invention to discover whether iCRH may be involved in the pathophysiology of certain skin conditions that are exacerbated by stress, such as eczema and urticaria. CRH could interact with the immune and the nervous systems and contribute to inflammation, possibly through activation of mast cells. Such a functional relation between central CRH, iCRH, neurons and mast cells could be important in normal physiology, in the context of hypersensitivity reactions, and in neuroimmunoendocrine or inflammatory syndromes. A further object of this invention was to test this hypothesis by examining the ability of CRH and stress to activate skin mast cells. It is an additional object of this invention to provide treatments that block or inhibit the effects of CRH on mast cell related skin disorders.